Effective wound repair requires a complex and integrated interplay of different cell types, pathways, and processes. Reepithelialization and restoration of barrier function is one requirement for successful healing and a process that is disrupted in chronic wounds. Genetic models have been pivotal for identification of genes that impinge on specific aspects wound healing, and we have obtained evidence that the developmental transcription factor Slug/Snail2 is a key regulator of epithelial outgrowth in vitro, ex vivo and in vivo. Slug and other members of the Snail family of proteins have been associated with regulation of adhesion and migration in development and cancer. The similarities between wound repair and developmental processes in the embryo are receiving increased attention, particularly with regard to the potential for shared regulatory pathways. Based on our evidence that Slug may contribute to regenerative processes in adult epidermis, this project will investigate the impact of Slug on keratinocyte outgrowth at wound borders. Our overall project goal is to understand mechanisms regulating the phenotypic plasticity of keratinocytes at wound margins during reepithelialization, and in doing so, shed light on processes that may be defective under conditions of impaired wound healing. In this proposal, our goal is to elucidate the events at the wound margin that are governed by Slug. We hypothesize that Slug plays central roles in regulating the partial and reversible epithelial-mesenchymal transition observed at wound margins. To test this hypothesis we will use a genetic model of Slug deficiency to 1) define the functional role of Slug in the keratinocyte activation program leading to cell proliferation and migration, 2) establish a molecular definition for the role of Slug in reepithelialization using microarray approaches and 3) establish whether elevated Slug expression augments wound repair in vivo using models of normal and impaired wound healing. These studies will provide information on the contributions of Slug to the functional and phenotypic plasticity required for successful reepithelialzation. Understanding key regulatory mechanisms in normal wound repair may identify new avenues for clinical intervention in medical conditions leading to impaired wound healing. [unreadable] [unreadable] [unreadable]